Journal of Exposure Science and Environmental Epidemiology (2015) 25, 119–120 © 2015 Nature America, Inc. All rights reserved 1559-0631/15
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LETTERS TO THE EDITOR
Cadmium exposure in inhabitants living in non-polluted area Journal of Exposure Science and Environmental Epidemiology (2015) 25, 119; doi:10.1038/jes.2014.37 Urinary cadmium (Cd) is widely used in epidemiological studies to measure Cd accumulation in the kidney, which is a critical organ for long-term Cd exposure. In general inhabitants, environmental Cd intake occurs through tobacco and foods grown in soil. Adams and Newcomb1 precisely reported the levels of blood and urinary Cd in relation to smoking status using data obtained from the National Health and Nutrition Examination Survey. In this article, the authors concluded that the application of blood and urinary Cd for studying Cd exposure should be done with caution, because there is an overlap in relation to exposure period. I previously reported the effect of Cd exposure on several renal biomarkers for workers by measuring blood and urinary Cd in spot urine, and concluded that urinary metallothionein and N-acetylbeta-D-glucosaminidase were more closely associated with urinary Cd than blood Cd in Cd-exposed workers whose mean urinary Cd level was o10 μg per g creatinine.2 Considering biological markers as dependent variables seems important to evaluate the relationship of Cd exposure with age and smoking. Regarding this point, Chaumont et al.3 conducted a baseline study of the background Cd exposure of the general population in Belgium and reported its relationship with urinary protein excretion. Although age, gender, smoking and survey year were used as the covariates for determining the effects of Cd exposure, Adams and Newcomb4 pointed out that dietary Cd intake from food information was not superior to the measurement of urinary Cd for the estimation of long-term Cd exposure. Contrary to their opinion, I suppose that dietary Cd intake exerts an important influence on Cd accumulation in the kidney, and it should be handled as one of the covariates in a baseline study, especially in a Cd-polluted area. This speculation was based on a recent Chinese study, which reported that the geometric mean value of U-Cd was around 2 μg per g creatinine.5 This geometric mean value was 3 to 4 times higher than the values reported by Chaumont et al. In a recent Korean study, Huang et al.6 reported that the mean urinary Cd of male inhabitants in current and former smokers was significantly higher than the urinary Cd in never smokers, which was basically in agreement with the results reported by Adams
and Newcomb. I also appreciate the precise information on the smoking duration and the daily number of cigarettes by Adams and Newcomb for the comparability of the results. There was no difference in the blood Cd levels between never smokers and former smokers in the Korean study, especially in subjects under 50 years old,6 which was the same as the result reported by Adams and Newcomb. Nordberg et al.7 reported the non-linear relationship between age and urinary Cd, and stratified information by sex and smoking status was presented by Adams and Newcomb in Cd non-polluted areas. The relevance of ethnicity should be investigated by an inter-cultural study. CONFLICT OF INTEREST The author declares no conflict of interest.
Tomoyuki Kawada1 Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan
1
REFERENCES 1 Adams SV, Newcomb PA. Cadmium blood and urine concentrations as measures of exposure: NHANES 1999-2010. J Expo Sci Environ Epidemiol 2014; 24: 163–170. 2 Kawada T, Tohyama C, Suzuki S. Significance of the excretion of urinary indicator proteins for a low level of occupational exposure to cadmium. Int Arch Occup Environ Health 1990; 62: 95–100. 3 Chaumont A, Voisin C, Deumer G, Haufroid V, Annesi-Maesano I, Roels H et al. Associations of urinary cadmium with age and urinary proteins: further evidence of physiological variations unrelated to metal accumulation and toxicity. Environ Health Perspect 2013; 121: 1047–1053. 4 Adams SV, Newcomb PA. Urinary cadmium as a marker of exposure in epidemiological studies. Environ Health Perspect 2013; 121: A296. 5 Liang Y, Lei L, Nilsson J, Li H, Nordberg M, Bernard A et al. Renal function after reduction in cadmium exposure: an 8-year follow-up of residents in cadmiumpolluted areas. Environ Health Perspect 2012; 120: 223–228. 6 Huang M, Choi SJ, Kim DW, Kim NY, Bae HS, Yu SD et al. Evaluation of factors associated with cadmium exposure and kidney function in the general population. Environ Toxicol 2013; 28: 563–570. 7 Nordberg GF, Fowler BA, Nordberg M, Friberg LT. Handbook on the Toxicology of Metals, 3rd edn. Academic Press: Burlington, MA, USA, 2007.
Urinary creatinine adjustment for uranium and kidney outcomes from lead workers Journal of Exposure Science and Environmental Epidemiology (2015) 25, 119–120; doi:10.1038/jes.2014.77
Shelley et al.1 reported that urinary adjustment by creatinine in nephrotoxic research had an effect on the association between uranium and kidney outcomes in lead workers. They used urinary
N-acetyl-beta-D-glucosaminidase (NAG), two types of estimated glomerular filtration rate (eGFR), or measured creatinine clearance as a dependent variable, and urinary uranium was used as an independent variable in combination with several associated factors for multiple regression analysis. Urinary uranium was measured from spot urine, by creatinine adjustment and from 4-hour urine collection. The authors concluded that creatinine adjustment should be done cautiously to determine the net
Letters to the Editor
120 association between uranium exposure and kidney outcomes. I fundamentally agree with their statistical procedure, but I have some concerns on their result. First, the authors handled the lead workers with a median value of blood lead of 21.5 mg/dl. In addition, the median value of urinary cadmium was 0.83 mg/g creatinine and the target subjects were assumed as population with low-level exposure to lead or cadmium. I previously reported that urinary NAG was also an early biological marker for renal effects,2 and the environmental exposure level was almost the same with Shelley’s population. Urinary uranium was associated with blood lead in their population, and I speculate that significant association between urinary uranium and urinary NAG after adjustment by several confounders is considered to be uranium association with kidney outcomes. NAG cannot pass through the glomerulus and urinary NAG is presented by a damage of renal proximal tubules. The same association was observed in measured creatinine clearance, and renal effect was supposed to be existed in both glomerulus and proximal tubules. As eGFR was derived from mathematical equation, and caution should be paid on its validity.3,4 Second, there is a variation in kidney function, and the time of 4-hour urine collection relates to study outcome for biological monitoring.5,6 This means that the lack of significance in samples of 4-hour urine collection cannot become a problem on creatinine adjustment. Although nephrotoxic evaluation seem to be difficult in early stage of renal damage, creatinine adjustment does not lose its meaning for the biological monitoring. Finally, please check the lower value of 95% confidence interval of beta coefficient between Ln-uranium mg/l and Ln-NAG. It was described as − 0.0002, and I suppose that it should be a positive number if there is a statistical significance. Anyway, Shelley et al.
presented the information on creatinine adjustment for biological monitoring of uranium exposure in combination with kidney outcomes. As the information is limited on this material, combined effect with other toxic substances should be precisely explored. CONFLICT OF INTEREST The author declares no conflict of interest.
Tomoyuki Kawada1 Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan
1
REFERENCES 1 Shelley R, Kim NS, Parsons PJ, Lee BK, Agnew J, Jaar BG et al. Uranium associations with kidney outcomes vary by urine concentration adjustment method. J Expo Sci Environ Epidemiol 2014; 24: 58–64. 2 Kawada T, Tohyama C, Suzuki S. Effects of cadmium and lead exposure on urinary N-acetyl-beta-D-glucosaminidase, beta 2-microglobulin and metallothionein of workers. Asia Pac J Public Health 1995; 8: 91–94. 3 Kawada T. Validating GFR estimating samples with clinical outcomes. Am J Kidney Dis 2014; 63: 859. 4 Kawada T. Estimated glomerular filtration rate by two equations and their relationship with metabolic syndrome. Clin Chim Acta 2014; 437: 220–221. 5 Akerstrom M, Barregard L, Lundh T, Sallsten G. Variability of urinary cadmium excretion in spot urine samples, first morning voids, and 24 h urine in a healthy non-smoking population: implications for study design. J Expo Sci Environ Epidemiol 2014; 24: 171–179. 6 Kawada T, Suzuki S, Koyama H. Concentration correction and standardization of some constituents in spot urine by using creatinine concentration in urine. Sangyo Igaku 1987; 29: 386–387.
www.nature.com/jes
LETTERS TO THE EDITOR
Cadmium exposure in inhabitants living in non-polluted area Journal of Exposure Science and Environmental Epidemiology (2015) 25, 119; doi:10.1038/jes.2014.37 Urinary cadmium (Cd) is widely used in epidemiological studies to measure Cd accumulation in the kidney, which is a critical organ for long-term Cd exposure. In general inhabitants, environmental Cd intake occurs through tobacco and foods grown in soil. Adams and Newcomb1 precisely reported the levels of blood and urinary Cd in relation to smoking status using data obtained from the National Health and Nutrition Examination Survey. In this article, the authors concluded that the application of blood and urinary Cd for studying Cd exposure should be done with caution, because there is an overlap in relation to exposure period. I previously reported the effect of Cd exposure on several renal biomarkers for workers by measuring blood and urinary Cd in spot urine, and concluded that urinary metallothionein and N-acetylbeta-D-glucosaminidase were more closely associated with urinary Cd than blood Cd in Cd-exposed workers whose mean urinary Cd level was o10 μg per g creatinine.2 Considering biological markers as dependent variables seems important to evaluate the relationship of Cd exposure with age and smoking. Regarding this point, Chaumont et al.3 conducted a baseline study of the background Cd exposure of the general population in Belgium and reported its relationship with urinary protein excretion. Although age, gender, smoking and survey year were used as the covariates for determining the effects of Cd exposure, Adams and Newcomb4 pointed out that dietary Cd intake from food information was not superior to the measurement of urinary Cd for the estimation of long-term Cd exposure. Contrary to their opinion, I suppose that dietary Cd intake exerts an important influence on Cd accumulation in the kidney, and it should be handled as one of the covariates in a baseline study, especially in a Cd-polluted area. This speculation was based on a recent Chinese study, which reported that the geometric mean value of U-Cd was around 2 μg per g creatinine.5 This geometric mean value was 3 to 4 times higher than the values reported by Chaumont et al. In a recent Korean study, Huang et al.6 reported that the mean urinary Cd of male inhabitants in current and former smokers was significantly higher than the urinary Cd in never smokers, which was basically in agreement with the results reported by Adams
and Newcomb. I also appreciate the precise information on the smoking duration and the daily number of cigarettes by Adams and Newcomb for the comparability of the results. There was no difference in the blood Cd levels between never smokers and former smokers in the Korean study, especially in subjects under 50 years old,6 which was the same as the result reported by Adams and Newcomb. Nordberg et al.7 reported the non-linear relationship between age and urinary Cd, and stratified information by sex and smoking status was presented by Adams and Newcomb in Cd non-polluted areas. The relevance of ethnicity should be investigated by an inter-cultural study. CONFLICT OF INTEREST The author declares no conflict of interest.
Tomoyuki Kawada1 Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan
1
REFERENCES 1 Adams SV, Newcomb PA. Cadmium blood and urine concentrations as measures of exposure: NHANES 1999-2010. J Expo Sci Environ Epidemiol 2014; 24: 163–170. 2 Kawada T, Tohyama C, Suzuki S. Significance of the excretion of urinary indicator proteins for a low level of occupational exposure to cadmium. Int Arch Occup Environ Health 1990; 62: 95–100. 3 Chaumont A, Voisin C, Deumer G, Haufroid V, Annesi-Maesano I, Roels H et al. Associations of urinary cadmium with age and urinary proteins: further evidence of physiological variations unrelated to metal accumulation and toxicity. Environ Health Perspect 2013; 121: 1047–1053. 4 Adams SV, Newcomb PA. Urinary cadmium as a marker of exposure in epidemiological studies. Environ Health Perspect 2013; 121: A296. 5 Liang Y, Lei L, Nilsson J, Li H, Nordberg M, Bernard A et al. Renal function after reduction in cadmium exposure: an 8-year follow-up of residents in cadmiumpolluted areas. Environ Health Perspect 2012; 120: 223–228. 6 Huang M, Choi SJ, Kim DW, Kim NY, Bae HS, Yu SD et al. Evaluation of factors associated with cadmium exposure and kidney function in the general population. Environ Toxicol 2013; 28: 563–570. 7 Nordberg GF, Fowler BA, Nordberg M, Friberg LT. Handbook on the Toxicology of Metals, 3rd edn. Academic Press: Burlington, MA, USA, 2007.
Urinary creatinine adjustment for uranium and kidney outcomes from lead workers Journal of Exposure Science and Environmental Epidemiology (2015) 25, 119–120; doi:10.1038/jes.2014.77
Shelley et al.1 reported that urinary adjustment by creatinine in nephrotoxic research had an effect on the association between uranium and kidney outcomes in lead workers. They used urinary
N-acetyl-beta-D-glucosaminidase (NAG), two types of estimated glomerular filtration rate (eGFR), or measured creatinine clearance as a dependent variable, and urinary uranium was used as an independent variable in combination with several associated factors for multiple regression analysis. Urinary uranium was measured from spot urine, by creatinine adjustment and from 4-hour urine collection. The authors concluded that creatinine adjustment should be done cautiously to determine the net
Letters to the Editor
120 association between uranium exposure and kidney outcomes. I fundamentally agree with their statistical procedure, but I have some concerns on their result. First, the authors handled the lead workers with a median value of blood lead of 21.5 mg/dl. In addition, the median value of urinary cadmium was 0.83 mg/g creatinine and the target subjects were assumed as population with low-level exposure to lead or cadmium. I previously reported that urinary NAG was also an early biological marker for renal effects,2 and the environmental exposure level was almost the same with Shelley’s population. Urinary uranium was associated with blood lead in their population, and I speculate that significant association between urinary uranium and urinary NAG after adjustment by several confounders is considered to be uranium association with kidney outcomes. NAG cannot pass through the glomerulus and urinary NAG is presented by a damage of renal proximal tubules. The same association was observed in measured creatinine clearance, and renal effect was supposed to be existed in both glomerulus and proximal tubules. As eGFR was derived from mathematical equation, and caution should be paid on its validity.3,4 Second, there is a variation in kidney function, and the time of 4-hour urine collection relates to study outcome for biological monitoring.5,6 This means that the lack of significance in samples of 4-hour urine collection cannot become a problem on creatinine adjustment. Although nephrotoxic evaluation seem to be difficult in early stage of renal damage, creatinine adjustment does not lose its meaning for the biological monitoring. Finally, please check the lower value of 95% confidence interval of beta coefficient between Ln-uranium mg/l and Ln-NAG. It was described as − 0.0002, and I suppose that it should be a positive number if there is a statistical significance. Anyway, Shelley et al.
presented the information on creatinine adjustment for biological monitoring of uranium exposure in combination with kidney outcomes. As the information is limited on this material, combined effect with other toxic substances should be precisely explored. CONFLICT OF INTEREST The author declares no conflict of interest.
Tomoyuki Kawada1 Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan
1
REFERENCES 1 Shelley R, Kim NS, Parsons PJ, Lee BK, Agnew J, Jaar BG et al. Uranium associations with kidney outcomes vary by urine concentration adjustment method. J Expo Sci Environ Epidemiol 2014; 24: 58–64. 2 Kawada T, Tohyama C, Suzuki S. Effects of cadmium and lead exposure on urinary N-acetyl-beta-D-glucosaminidase, beta 2-microglobulin and metallothionein of workers. Asia Pac J Public Health 1995; 8: 91–94. 3 Kawada T. Validating GFR estimating samples with clinical outcomes. Am J Kidney Dis 2014; 63: 859. 4 Kawada T. Estimated glomerular filtration rate by two equations and their relationship with metabolic syndrome. Clin Chim Acta 2014; 437: 220–221. 5 Akerstrom M, Barregard L, Lundh T, Sallsten G. Variability of urinary cadmium excretion in spot urine samples, first morning voids, and 24 h urine in a healthy non-smoking population: implications for study design. J Expo Sci Environ Epidemiol 2014; 24: 171–179. 6 Kawada T, Suzuki S, Koyama H. Concentration correction and standardization of some constituents in spot urine by using creatinine concentration in urine. Sangyo Igaku 1987; 29: 386–387.
